Autoinhibition of mdmx by intramolecular p53 mimicry pnas. One strategy to achieve this is to target the p53 regulators mdm2 and mdmx. The current generation of mdm2 inhibitors does not inhibit mdmx. Dual inhibition of mdmx and mdm2 as a therapeutic strategy. Aberrant murine double minute 2 mdm2 expression restricts tumor protein p53 tp53 and its tumorsuppressor functions, leaving cells more susceptible to oncogenic mutations and transformation. Current medicinal chemistry, 2012, 19, 57055725 5705. The homologs mdm2 and mdmx have been shown tobe the major, essential negative regulators of p53. Mdm proteins, p53independent oncogenic functions of. The mdm2 and mdmx also known as hdmx and mdm4 proteins are deregulated in many human cancers and exert their oncogenic activity. This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by mdm2 overexpression, control of mutant or wildtype p53.
Mdm2 and mdmx inhibitor restores p53 functioning in. Mdm2 and mdmx inhibitor restores p53 functioning in cancers with wildtype p53 leave a reply p53 is a tumor suppressor gene that pauses cell division to allow for repair of gene damage, and triggers. Numerous genetic experiments described above helped to define p53 as an important target of mdm2 and mdmx in cell survival and in development. Homozygous deletion of mdm2 results in lethality at the. Wahl abstract the mdm2 and mdmx also known as hdmx and mdm4 proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. In human cancers, the tp53 gene is frequently mutated or deleted, or the wildtype p53. A dimethylbromobenzenecysteine stapled peptide dual. Mdm2 and mdmx in cancer and development sciencedirect.
Efforts to develop mdmx inhibitors have been largely unsuccessful, indicating gaps in our understanding of the structure and regulation of mdmx. Numerous genetic experiments described above helped to define p53 as an important target of mdm2 and mdmx in cell survival and in. Mdm2 and mdmx also regulate p53mediated tumor suppression. These two proteins are best understood as negative regulators of the p53 tumor suppressor, although they may have additional p53 independent roles. Mdm2, mdmx and p53 in oncogenesis and cancer therapy. The p53 tumor suppressor also has an important role in cancer therapy, with p53mediated. The p53 tumor suppressor protein and its major negative regulators mdm2 and mdmx oncoproteins form the mdm2 mdmx p53 circuitry, which plays critical roles in regulating cancer cell growth. Definition of mdm2mdmx inhibitor alrn6924 nci drug. The activity and level of the tumor suppressor protein p53 is negatively regulated by the e3 ligase mdm2, which controls both its ability to trans. This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by mdm2 overexpression, control of mutant or wildtype p53 function by mdm2 and mdmx, p53 mutation in hereditary cancer and structural aspects that activate mutant p53 which can be targeted by drug therapy. Targeting p53mdm2mdmx loop for cancer therapy europe pmc.
Effect of the mdm2 antagonist rg7112 on the p53 pathway in. Mdm2 oncogene as a novel target for human cancer therapy. An orally available inhibitor of both murine double minute 2 mdm2 and murine double minute x mdmx, with potential antineoplastic activity. Aberrant murine double minute 2 mdm2 expression restricts tumor protein p53 tp53 and its tumor. Like mdm2, mdmx is overexpressed in many cancers, especially those of breast, colon, and lung. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a. Mdm2 and mdmx are known to bind together, and play multifaceted, nonredundant roles in. Specifically, atsp7041 binds both mdm2 and mdmx with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly. Between june 3, and dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. Mdm2 achieves this repression by binding to and blocking the nterminal transactivation domain of p53. Mdm2 is a p53 responsive genethat is, its transcription can be activated by p53.
Pmc free article shadfan m, lopezpajares v, yuan zm. In normal cells, mdm2 and mdmx suppress p53 activity,but in the event of cellular stress, they. However, half of all human tumors expresswildtypep53,anditsactivationbyantagonizing. The mdm2 oncoprotein binds to the p53 tumor suppressor protein and serves as a negative regulator of p53. Mutant p53 and mdm2 in cancer in cludes1 9c haptersth adt iscussth ea ctivation of diverse oncogenic pathways consequent to p53 mutation and overexpression of mdm2 and mdmx and their splice variants.
Jan 10, 20 mdm2, mdmx and p53 in oncogenesis and cancer therapy. These data indicate that wildtype p53 is a valid therapeutic target, and that reactivation of p53 via selective targeting of either mdm2 or mdmx is a viable strategy for cancer therapy. Cytoplasmic tethering is involved in synergistic inhibition. Mdmx is commonly overexpressed in tumors, and its upregulation has been shown to promote tumor formation danovi et al. Direct, competitive comparison of linear, monocyclic, and. Mdm2, mdmx and p53 in oncogenesis and cancer therapy rays pneumonitis rp and radiation fibrosis rf are two doselimiting toxicities encephalitogenic myelin oligodendrocyte. Amplification of mdmx and overexpression of mdm2 contribute.
Also, p53 isoforms differ in their affinity for p53 responsive elements re in the promoters of their target genes. Here, we report a potent and selective dual inhibitor of mdm2 and mdmx, atsp7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Given that mdm2 and mdm4 inhibit p53 activities to promote tumor development, small. Awakening p53 in vivo by dpeptidesfunctionalized ultrasmall nanoparticles. We assessed the genetic instability at p53, mdmx and mdm2 using high. For more than 25 years, mdm2 and its homolog mdmx also known as mdm4 have been shown to exert oncogenic activity. Thus, a negative feedback loop exists between p53 and mdm2 that has been confirmed by elegant studies at the singlecell level see lahav 2008. Additionally, its function is abrogated by the overexpression of mdm2 and mdmx in a significant proportion of tumors retaining wildtype p53 1,2. Request pdf mdm2, mdmx and p53 in oncogenesis and cancer therapy the mdm2 and mdmx also known as hdmx and mdm4 proteins.
Mdm2 and mdmx are regulators of p53 function mdm2 is an ubiquitin ligase that tags p53 for destruction in the proteasome. These inhibitors could displace p53 from mdm2 in vitro with. Jul 26, 2017 mdm2 and mdmx are regulators of p53 function mdm2 is an ubiquitin ligase that tags p53 for destruction in the proteasome. Mdm2 and mdmx execute their oncogenic activity mainly by negatively regulating the stability and activity of the p53 protein in a feedback fashion fig. The mdm2 p53 autoregulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti mdm2 drug discovery. Diabolically for cancer, interference with the capacity of mdm2 to degrade p53, through alteration of mdm2 isoform levels, can promote the accumulation of not only wt p53, but also its. Mdm2 and mdmx inhibitor restores p53 functioning in cancers. Therefore, their therapeutic efficacy will be influenced by. However, half of all human tumors express wildtype p53, and its activation by antagonizing its negative regulator murine double minute 2 mdm2 might offer a new therapeutic strategy.
This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by mdm2 overexpression, control of mutant or wildtype p53 function by mdm2 and mdmx, p53 mutation in hereditary cancer, and structural aspects that activate mutant p53 which can be targeted by drug therapy. Benzimidazoles downregulate mdm2 and mdmx and activate p53. Apr 14, 2015 mdmx protein is a critical regulator of p53 and a novel drug target. Mdm2 is an important negative regulator of the p53. The p53 tumor suppressor has an important role in cancer therapy, with p53mediated cell growth arrest andor apoptosis being major mechanisms of action for many clinically used cancer chemotherapeutic. A tumorsuppressor pathway that is often disrupted in cancer 1. Ribosomal biogenesis is tightly associated with cellular activities, such as growth, proliferation, and cell cycle progression.
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as dna repair, cell cycle, apoptosis, angiogenesis, and senescence. Mdm gene amplification andor overexpression have been observed in a. Vassilev discovery oncology, roche research center, hoffmannla roche inc. Mdm2 and mdmx heterodimerize to facilitate mdm2mediated ubiquitination and degradation of p53. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a few modulators regulating its expression and function, with murine double minute 2 mdm2 playing a key role in this regard. The importance of the p53mdm2mdmx relationship to a tumor phenotype has also been demonstrated genetically.
Thus when p53 is stabilized, the transcription of mdm2 is. Mutant p53 and mdm2 in cancer in cludes1 9c haptersth adt iscussth ea ctivation of. Mdm2, mdmx and p53 in oncogenesis and cancer therapy mark wade 1, yao. Perturbations in ribosomal biogenesis can initiate socalled nucleolar stress. A mrna expression analysis of mdmx in human cancers using the cancer genome atlas tcga data sets and b mdmx and mdm2 mrna expression in hematopoietic stem hsc and granulocytemonocytic progenitorenriched gmp cells from acute myeloid leukemia aml patients n 14 and healthy. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein mdm2. Mouse double minute 2 homolog mdm2 also known as e3 ubiquitinprotein ligase mdm2 is a protein that in humans is encoded by the mdm2 gene. Mdmx protein is a critical regulator of p53 and a novel drug target. These two proteins are best understood as negative regulators of the p53 tumor. Request pdf mdm2, mdmx and p53 in oncogenesis and cancer therapy the mdm2 and mdmx also known as hdmx and mdm4 proteins are deregulated in many human cancers and exert their.
The p53 tumor suppressor plays a central role in the prevention of tumorigenesis. The critical role of the tumor suppressor p53 is illustrated by the fact that nearly 50% of human malignant neoplasms carry mutations in the p53 gene tp53. By preventing mdm2p53 and mdmxp53 interactions, p53 activity is restored, which leads to p53mediated induction of tumor cell apoptosis. Mdm2 mdmx and p53 in oncogenesis and cancer therapy. Understanding the dysregulation of mdm2 and mdmx in human cancers and how they function either together or separately in. Validation of mdmx as a therapeutic target for reactivating p53 in. Mdm2 and mdmx, negative regulators of p53 function. The process through which ribosomal proteins rps transduce nucleolar stress signals via mdm2 to p53 has been described as a crucial tumorsuppression mechanism.
Identification of novel inhibitors of p53mdm2 interaction facilitated by pharmacophorebased virtual screening combining molecular docking strategy. Pdf the mdm2p53 pathway revisited semantic scholar. Mdm2 and mdmx are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid. Potential for treatment of liposarcomas with the mdm2. Several pharmacological strategies have been proposed for the activation of wildtype p53 table 4. The murine double minute 2 mdm2 and mdmx represent two important cellular regulators of p53. Jan 27, 2016 mdm2 and mdmx are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Mutant p53 and mdm2 in cancer swati palit deb, sumitra. The importance of the p53 mdm2 mdmx relationship to a tumor phenotype has also been demonstrated genetically. Amplification of mdmx and overexpression of mdm2 contribute to. Mdm2 also contributes to malignant transformation and cancer. The reactivation of wildtype p53 could potentially improve the treatment of many cancer patients. The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in cancer. Targeting mdm2 and mdm4 in cancer therapy clinical cancer.
Genetic abnormalities detected by multicolor fish in primary breast cancer. Mutant p53 and mdm2 in cancer swati palit deb, sumitra deb. Swati palitdeb sumitra deb editors mutant p53 and mdm2 in cancer. Dual inhibition of mdmx and mdm2 as a therapeutic strategy in. In normal cells, mdm2 and mdmx suppress p53 activity,but in the event of cellular stress, they themselves must be inhibited so that p53 may respond to the stress. Diabolically for cancer, interference with the capacity of mdm2 to degrade p53, through alteration of mdm2 isoform levels, can promote the accumulation of not only wt p53, but also its mutant form zheng et al. Myc tumors is eventually compromised by the emergence of. Wahl abstract the mdm2 and mdmx also known as hdmx and mdm4 proteins are deregulated. Both mdm2 and mdmx function as powerful oncogenes and are commonly overexpressed in some cancers, including sarcoma 20% and breast cancer 15%. Frontiers clinical overview of mdm2xtargeted therapies. Mdm2 itself is in turn regulated by p53, as there are p53 response elements located in the promoter of the mdm2 gene barak et al. Mutant p53 and mdm2 in cancer swati palit deb springer. Upon oral administration, alrn6924 binds to both mdm2 and mdmx and interferes with their interaction with the transcriptional activation domain of the tumor suppressor protein p53.
The p53 tumor suppressor protein and its major negative regulators mdm2 and mdmx oncoproteins form the mdm2mdmxp53 circuitry, which plays critical roles in regulating cancer cell growth. The p53 tumor suppressor also has an important role in cancer therapy, with p53 mediated apoptosis being a major mechanism of action for many clinically used cancer chemotherapeutic agents and radiation therapy. The first potent and selective smallmolecule mdm2 antagonists, the nutlins, were identified from a class of cisimidazoline compounds. Weisi wang, xiaolei zhu, xueqin hong, lin zheng, hong zhu, yongzhou hu. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Request pdf mdm2, mdmx and p53 in oncogenesis and cancer therapy the mdm2 and mdmx also known as hdmx and mdm4 proteins are deregulated in many human cancers and exert their oncogenic. Therefore, their therapeutic efficacy will be influenced by poorly characterized mdmx functional status in tumors. Temporal activation of p53 by a specific mdm2 inhibitor is. The intimate relationship between mdm2 and p53 was clearly revealed in studies in which mdm2 was knocked out in the mouse germline. Nutlin3, the smallmolecule inhibitor of mdm2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wildtype p53.
Swati palitdeb sumitra deb editors mutant p53 and mdm2 in. Comparatively, a treatment of the cells with 100 n m 4ohtamoxifen oht decreased cell number to 40% of the control without a concomitant decrease in the p53 levels suggesting a differential. Dec 24, 2019 mdm2, mdmx and p53 in oncogenesis and cancer therapy. Structurebased design of novel inhibitors of the mdm2p53.
Mdm2p53 complex 25, we have designed spirooxindoles fig. Mdm2, mdmx and p53 in oncogenesis and cancer therapy ncbi. Mdm2 and mdmx heterodimerize to facilitate mdm2 mediated ubiquitination and degradation of p53. The tumor suppressor p53 is believed to be the mostly studied molecule in modern biomedical research.